A predictive coding framework of allostatic–interoceptive overload in frontotemporal dementia
Authors: Joaquin A. Migeot, Claudia A. Duran-Aniotz, Camilo M. Signorelli, Olivier Piguet, Agustín Ibáñez
Journal: Trends in Neurosciences (2022)

Allostatic–interoceptive predictive coding frameworks suggest that regulation of the body's internal milieu is required to predict and meet the needs generated from environmental demands before they arise.A multilevel organization of allostatic–interoceptive measures is proposed across cerebral, cardiocerebral, peripheral, and psychological levels.Behavioral variant frontotemporal dementia (bvFTD) is characterized by disparate autonomic, behavioral, and pathophysiological manifestations that seem to parallel multilevel measures of an allostatic–interoceptive overload.Under a predictive coding model, the allostatic–interoceptive deficits are explained by a mismatch between top-down and bottom-up predictions and prediction errors at multilevel hierarchies impaired in bvFTD, providing a novel framework for characterization, diagnosis, and interventions in bvFTD patients. Recent allostatic–interoceptive explanations using predictive coding models propose that efficient regulation of the body's internal milieu is necessary to correctly anticipate environmental needs. We review this framework applied to understanding behavioral variant frontotemporal dementia (bvFTD) considering both allostatic overload and interoceptive deficits. First, we show how this framework could explain divergent deficits in bvFTD (cognitive impairments, behavioral maladjustment, brain atrophy, fronto-insular-temporal network atypicality, aberrant interoceptive electrophysiological activity, and autonomic disbalance). We develop a set of theory-driven predictions based on levels of allostatic interoception associated with bvFTD phenomenology and related physiopathological mechanisms. This approach may help further understand the disparate behavioral and physiopathological dysregulations of bvFTD, suggesting targeted interventions and strengthening clinical models of neurological and psychiatric disorders. Recent allostatic–interoceptive explanations using predictive coding models propose that efficient regulation of the body's internal milieu is necessary to correctly anticipate environmental needs. We review this framework applied to understanding behavioral variant frontotemporal dementia (bvFTD) considering both allostatic overload and interoceptive deficits. First, we show how this framework could explain divergent deficits in bvFTD (cognitive impairments, behavioral maladjustment, brain atrophy, fronto-insular-temporal network atypicality, aberrant interoceptive electrophysiological activity, and autonomic disbalance). We develop a set of theory-driven predictions based on levels of allostatic interoception associated with bvFTD phenomenology and related physiopathological mechanisms. This approach may help further understand the disparate behavioral and physiopathological dysregulations of bvFTD, suggesting targeted interventions and strengthening clinical models of neurological and psychiatric disorders. In recent years, predictive coding theories linking allostasis (see Glossary) and interoception have gained considerable attention in neuroscience [1.Petzschner F.H. et al.Computational models of interoception and body regulation.Trends Neurosci. 2021; 44: 63-76Abstract Full Text Full Text PDF PubMed Google Scholar, 2.Nord C.L. Garfinkel S.N. Interoceptive pathways to understand and treat mental health conditions.Trends Cogn. Sci. 2022; 26: 499-513Abstract Full Text Full Text PDF PubMed Google Scholar, 3.Quigley K.S. et al.Functions of interoception: from energy regulation to experience of the self.Trends Neurosci. 2021; 44: 29-38Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar, 5.Schulkin J. Sterling P. Allostasis: a brain-centered, predictive mode of physiological regulation.Trends Neurosci. 2019; 42: 740-752Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 6.Sterling P. Homeostasis vs allostasis implications for brain function and mental disorders.JAMA Psychiatry. 2014; 71: 1192-1193Crossref PubMed Scopus (48) Google Scholar]. Predictive coding refers to the assumption that the brain is actively and continuously anticipating and updating environmental (exteroception) and internal (interoception) models. One advantage of predictive coding is that it can be instantiated across several biological substrates and hierarchies (Figure 1A ). Allostasis refers to a process of continuous adjustment of the organism milieu (e.g., blood pressure, temperature) to anticipate, and adapt to, environmental changes [7.Guidi J. et al.Allostatic load and its impact on health: a systematic review.Psychother. Psychosom. 2020; 90: 11-27Crossref PubMed Scopus (147) Google Scholar] and interoception to the sensing of the body signals [8.Tsakiris M. Critchley H. Interoception beyond homeostasis: affect, cognition and mental health.Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2016; 371: 20160002Crossref PubMed Scopus (0) Google Scholar]. Together, allostatic and interoceptive processes jointly contribute to meeting the upcoming internal and environmental demands through the updating of internal model predictions (e.g., increasing blood supply in a fight or flight situation, lowering heart rate when going to sleep, and reducing blood flow to skin capillaries to preserve core temperature, Figure 1B). In such models, sensory inputs are represented in low levels of the neural and computational hierarchy, while complex interpretations constitute higher levels. Based on statistical assumptions, each higher level predicts the activity in the lower level. The difference between the prediction (e.g., anticipation of feeling pain when getting vaccinated, thus tensing the arm muscles) and the actual sensory input (e.g., not even feeling the needle) generates a prediction error, which is sent back to the higher level in order to correct future predictions (e.g., relaxing arm muscles when receiving future vaccines). The predictive coding of allostasis and interoception may help understand dementia [9.Kocagoncu E. et al.Evidence and implications of abnormal predictive coding in dementia.Brain. 2021; 144: 3311-3321Crossref PubMed Scopus (5) Google Scholar,10.Birba A. et al.Allostatic-interoceptive overload in frontotemporal dementia.Biol. Psychiatry. 2022; 92: 54-67Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] and other neurological or psychiatric disorders [2.Nord C.L. Garfinkel S.N. Interoceptive pathways to understand and treat mental health conditions.Trends Cogn. Sci. 2022; 26: 499-513Abstract Full Text Full Text PDF PubMed Google Scholar,11.Barrett L.F. et al.An active inference theory of allostasis and interoception in depression.Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2016; 371: 20160011Crossref PubMed Google Scholar]. In this article, we review the evidence to extend these models to behavioral variant frontotemporal dementia (bvFTD), which is the most common clinical presentation of frontotemporal lobar degeneration. It is characterized by early changes in personality, social behavior, self-regulation, executive functions, motivation, and emotional regulation [12.Piguet O. et al.Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management.Lancet Neurol. 2011; 10: 162-172Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 13.Piguet O. Kumfor F. Frontotemporal dementias: main syndromes and underlying brain changes.Curr. Opin. Neurol. 2020; 33: 215-221Crossref PubMed Scopus (6) Google Scholar, 14.Possin K.L. et al.Dissociable executive functions in behavioral variant frontotemporal and Alzheimer dementias.Neurology. 2013; 80: 2180-2185Crossref PubMed Scopus (76) Google Scholar]. bvFTD presents a pattern of progressive neurodegeneration involving fronto-temporo-insular regions [15.Kril J.J. Halliday G.M. Clinicopathological staging of frontotemporal dementia severity: correlation with regional atrophy.Dement. Geriatr. Cogn. Disord. 2004; 17: 311-315Crossref PubMed Scopus (0) Google Scholar]. These neurocognitive early changes could be the consequence of malfunctions in the dynamics of the allostatic–interoceptive process [10.Birba A. et al.Allostatic-interoceptive overload in frontotemporal dementia.Biol. Psychiatry. 2022; 92: 54-67Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Of note, alterations of allostasis and interoception have been observed across neurodegenerative conditions and in other variants of FTD. For instance, convergent evidence supports an allostatic overload in Alzheimer's disease, and interoceptive deficits are observed in other neurodegenerative conditions such as Parkinson's disease and multiple sclerosis (Box 1). Despite these related and transnosological alterations, we would argue that the proposed framework seems fairly specific to bvFTD: bvFTD's multimodal compromise of autonomic-interoceptive pathways, the allostatic overload observed across different levels, and the abnormal responses to environmental demands distinctively fit with an allostatic–interoceptive overload account.Box 1Transnosological allostatic–interoceptive overload and bvFTDBoth allostasis and interoception are dimensional processes that are compromised in many neurodegenerative conditions.Allostatic load is closely related to Alzheimer's disease pathophysiology, specifically regarding the bidirectional association between impaired insulin signaling and allostatic overload [121.De Felice F.G. et al.Impaired insulin signalling and allostatic load in Alzheimer disease.Nat. Rev. Neurosci. 2022; 23: 215-230Crossref PubMed Scopus (3) Google Scholar]. Lifestyle and social factors during life contribute to the allostatic load, which lead to allostatic overload when these become chronically harmful. Such state may trigger pathophysiological changes in the brain, including oxidative stress and chronic inflammation, leading to insulin resistance and predisposing the organism to Alzheimer's disease [121.De Felice F.G. et al.Impaired insulin signalling and allostatic load in Alzheimer disease.Nat. Rev. Neurosci. 2022; 23: 215-230Crossref PubMed Scopus (3) Google Scholar]. These alternative approaches to the traditional amyloid cascade hypothesis consider allostatic load as a crucial factor associated with the development and progression of Alzheimer's disease [122.Luczkowski M. "No screams and cries will convince us that white is white and black is black", an ode to the defenders of amyloid cascade hypothesis of Alzheimer's disease.Coord. Chem. Rev. 2016; 327-328: 35-42Crossref Scopus (6) Google Scholar].bvFTD appears to be the only neurodegenerative disease with systematic (behavioral, peripherical, HEP, and neurofunctional) impairments of autonomic and interoceptive dimensions. Such interoceptive dysregulations, however, are also present in other neurodegenerative conditions [123.Bonaz B. et al.Diseases, disorders, and comorbidities of interoception.Trends Neurosci. 2021; 44: 39-51Abstract Full Text Full Text PDF PubMed Google Scholar]. Although not without conflicting results, individuals with Alzheimer's disease tend to present impaired performance in interoceptive tasks [28.Abrevaya S. et al.At the heart of neurological dimensionality: cross-nosological and multimodal cardiac interoceptive deficits.Psychosom. Med. 2020; 82: 850-861Crossref PubMed Scopus (8) Google Scholar] along with abnormal modulations of the HEP, in addition to deficits in interoceptive awareness and learning [124.Garcia-Cordero I. et al.Metacognition of emotion recognition across neurodegenerative diseases.Cortex. 2021; 137: 93-107Crossref PubMed Scopus (6) Google Scholar]. Moreover, cardiac interoception deficits are also present in Parkinson's disease [125.Ricciardi L. et al.Know thyself: exploring interoceptive sensitivity in Parkinson's disease.J. Neurol. Sci. 2016; 364: 110-115Abstract Full Text Full Text PDF PubMed Google Scholar,126.Christopher L. et al.Uncovering the role of the insula in non-motor symptoms of Parkinson's disease.Brain. 2014; 137: 2143-2154Crossref PubMed Scopus (0) Google Scholar], which may help distinguish among postural instability/gait difficulty and tremor dominant variants [127.Santangelo G. et al.Interoceptive processing deficit: a behavioral marker for subtyping Parkinson's disease.Parkinsonism Relat. Disord. 2018; 53: 64-69Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Similarly, interoceptive deficits in multiple sclerosis [29.Salamone P.C. et al.Altered neural signatures of interoception in multiple sclerosis.Hum. Brain Mapp. 2018; 39: 4743-4754Crossref PubMed Scopus (11) Google Scholar] are linked to cardinal fatigue symptoms [128.Gonzalez Campo C. et al.Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities.Mult. Scler. 2020; 26: 1845-1853Crossref PubMed Scopus (19) Google Scholar]. Thus, neurodegeneration spreading over core or bordering interoceptive hubs across neurodegenerative diseases can lead to multiple dimensional deficits.Despite the presence of allostatic and interoceptive alterations in many neurodegenerative diseases, combined allostatic–interoceptive deficits are distinctively specific to bvFTD. The systematic affection of autonomic–interoceptive pathways combined with abnormal responses to environmental demands in bvFTD uniquely fits the allostatic–interoceptive overload account. Based on these antecedents, sui generis neurodegeneration-triggered deficits in bvFTD would influence imprecise interoceptive signals and lower precision, leading to an allostatic overload related with behavioral and neurocognitive manifestations. Both allostasis and interoception are dimensional processes that are compromised in many neurodegenerative conditions. Allostatic load is closely related to Alzheimer's disease pathophysiology, specifically regarding the bidirectional association between impaired insulin signaling and allostatic overload [121.De Felice F.G. et al.Impaired insulin signalling and allostatic load in Alzheimer disease.Nat. Rev. Neurosci. 2022; 23: 215-230Crossref PubMed Scopus (3) Google Scholar]. Lifestyle and social factors during life contribute to the allostatic load, which lead to allostatic overload when these become chronically harmful. Such state may trigger pathophysiological changes in the brain, including oxidative stress and chronic inflammation, leading to insulin resistance and predisposing the organism to Alzheimer's disease [121.De Felice F.G. et al.Impaired insulin signalling and allostatic load in Alzheimer disease.Nat. Rev. Neurosci. 2022; 23: 215-230Crossref PubMed Scopus (3) Google Scholar]. These alternative approaches to the traditional amyloid cascade hypothesis consider allostatic load as a crucial factor associated with the development and progression of Alzheimer's disease [122.Luczkowski M. "No screams and cries will convince us that white is white and black is black", an ode to the defenders of amyloid cascade hypothesis of Alzheimer's disease.Coord. Chem. Rev. 2016; 327-328: 35-42Crossref Scopus (6) Google Scholar]. bvFTD appears to be the only neurodegenerative disease with systematic (behavioral, peripherical, HEP, and neurofunctional) impairments of autonomic and interoceptive dimensions. Such interoceptive dysregulations, however, are also present in other neurodegenerative conditions [123.Bonaz B. et al.Diseases, disorders, and comorbidities of interoception.Trends Neurosci. 2021; 44: 39-51Abstract Full Text Full Text PDF PubMed Google Scholar]. Although not without conflicting results, individuals with Alzheimer's disease tend to present impaired performance in interoceptive tasks [28.Abrevaya S. et al.At the heart of neurological dimensionality: cross-nosological and multimodal cardiac interoceptive deficits.Psychosom. Med. 2020; 82: 850-861Crossref PubMed Scopus (8) Google Scholar] along with abnormal modulations of the HEP, in addition to deficits in interoceptive awareness and learning [124.Garcia-Cordero I. et al.Metacognition of emotion recognition across neurodegenerative diseases.Cortex. 2021; 137: 93-107Crossref PubMed Scopus (6) Google Scholar]. Moreover, cardiac interoception deficits are also present in Parkinson's disease [125.Ricciardi L. et al.Know thyself: exploring interoceptive sensitivity in Parkinson's disease.J. Neurol. Sci. 2016; 364: 110-115Abstract Full Text Full Text PDF PubMed Google Scholar,126.Christopher L. et al.Uncovering the role of the insula in non-motor symptoms of Parkinson's disease.Brain. 2014; 137: 2143-2154Crossref PubMed Scopus (0) Google Scholar], which may help distinguish among postural instability/gait difficulty and tremor dominant variants [127.Santangelo G. et al.Interoceptive processing deficit: a behavioral marker for subtyping Parkinson's disease.Parkinsonism Relat. Disord. 2018; 53: 64-69Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Similarly, interoceptive deficits in multiple sclerosis [29.Salamone P.C. et al.Altered neural signatures of interoception in multiple sclerosis.Hum. Brain Mapp. 2018; 39: 4743-4754Crossref PubMed Scopus (11) Google Scholar] are linked to cardinal fatigue symptoms [128.Gonzalez Campo C. et al.Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities.Mult. Scler. 2020; 26: 1845-1853Crossref PubMed Scopus (19) Google Scholar]. Thus, neurodegeneration spreading over core or bordering interoceptive hubs across neurodegenerative diseases can lead to multiple dimensional deficits. Despite the presence of allostatic and interoceptive alterations in many neurodegenerative diseases, combined allostatic–interoceptive deficits are distinctively specific to bvFTD. The systematic affection of autonomic–interoceptive pathways combined with abnormal responses to environmental demands in bvFTD uniquely fits the allostatic–interoceptive overload account. Based on these antecedents, sui generis neurodegeneration-triggered deficits in bvFTD would influence imprecise interoceptive signals and lower precision, leading to an allostatic overload related with behavioral and neurocognitive manifestations. We first review the available evidence and propose the hypothesis that bvFTD may be characterized by an imbalance of an allostatic–interoceptive system, with manifestations across cerebral, cardiocerebral, peripheral, and psychological dimensions. Then, we propose a set of theory-driven predictions in bvFTD, which are subsumed into a multidimensional framework integrating neurocognitive and physiological markers by multimodal assessments of allostatic interoceptive inference. Under such a framework, the cognitive and behavioral impairments of bvFTD are associated with: (i) brain structural and connectivity deficits among critical allostatic–interoceptive brain hubs, (ii) altered interoceptive electrophysiological activity, and (iii) allostatic overload at biomarker levels. Such a multidimensional framework may help further understand the disparate behavioral and physiopathological dysregulations of bvFTD within a predictive coding account, suggesting targeted interventions and strengthening clinical models of neurological and psychiatric disorders. Allostatic–interoceptive predictive coding frameworks [1.Petzschner F.H. et al.Computational models of interoception and body regulation.Trends Neurosci. 2021; 44: 63-76Abstract Full Text Full Text PDF PubMed Google Scholar, 2.Nord C.L. Garfinkel S.N. Interoceptive pathways to understand and treat mental health conditions.Trends Cogn. Sci. 2022; 26: 499-513Abstract Full Text Full Text PDF PubMed Google Scholar, 3.Quigley K.S. et al.Functions of interoception: from energy regulation to experience of the self.Trends Neurosci. 2021; 44: 29-38Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar, 5.Schulkin J. Sterling P. Allostasis: a brain-centered, predictive mode of physiological regulation.Trends Neurosci. 2019; 42: 740-752Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 6.Sterling P. Homeostasis vs allostasis implications for brain function and mental disorders.JAMA Psychiatry. 2014; 71: 1192-1193Crossref PubMed Scopus (48) Google Scholar] can offer novel neurocognitive and physiological accounts of allostasis, integrating multimodal sources of information about the body state [16.McEwen B.S. et al.Mechanisms of stress in the brain.Nat. Neurosci. 2015; 18: 1353-1363Crossref PubMed Scopus (728) Google Scholar]. Importantly, such frameworks open new possibilities for assessing brain–body–environment synergetic interactions in health and disease [17.Ibanez A. The mind's golden cage and cognition in the wild.Trends Cogn. Sci. 2022; https://doi.org/10.1016/j.tics.2022.07.008Abstract Full Text Full Text PDF Google Scholar], which can be integrated into a profile of allostatic–interoceptive manifestations at cerebral, cardiocerebral, peripheral, and psychological levels (Figure 2). Neuroimaging techniques have identified a domain-general allostatic–interoceptive network (AIN) that integrates visceromotor and interoceptive processes into a multimodal network (Figure 2A). This network connects a wide range of cognitive domains such as memory, executive function, emotion processing, and cognitive control, with allostatic load [4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar]. The AIN involves a large-scale brain network, the 'neural backbone' of the brain's coordinated neural activity. This network is composed of specific hubs of the salience network (bilateral ventral and dorsal anterior insula, anterior cingulate cortex, ventral striatum, thalamus, central nucleus of the amygdala, hypothalamus, and brainstem) and default mode network (bilateral angular gyrus, precuneus, hippocampus, and medial prefrontal cortices). The allostatic–interoceptive system, which is neuroanatomically defined by the AIN [4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar,18.McEwen B.S. Allostasis, allostatic load, and the aging nervous system: role of excitatory amino acids and excitotoxicity.Neurochem. Res. 2000; 25: 1219-1231Crossref PubMed Google Scholar], seems to maintain the neurocognitive balance based on interoceptive information. Specifically, the limbic cortices project to the hypothalamus and brainstem nuclei that monitor neuroendocrine, autonomic, and immune systems. These can be interpreted as anatomical paths for prediction signals from limbic cortices. Also, under a predictive coding interpretation, the hypothalamus and brainstem nuclei send signals that carry predictions of sensory outcomes of visceromotor changes to the primary interoceptive cortices. In parallel, internal sensory inputs from the body are projected through the vagus nerve to the primary interoceptive cortices, where both prediction signals and sensory inputs are contrasted, resulting in an interoceptive prediction error [4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar] (Figure 2A). As such, the AIN regulates cardiocerebral and peripheral activity that together have an impact on psychological and cognitive responses to the environment. For example, adults with a history of infant regulatory problems present selectively aberrant default mode and salience networks (AIN subnetworks) assessed with resting-state functional magnetic resonance imaging (rsfMRI) connectivity [19.Bäuml J.G. et al.The default mode network mediates the impact of infant regulatory problems on adult avoidant personality traits.Biol. Psychiatry Cogn. Neurosci. Neuroimaging. 2019; 4: 333-342Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The AIN and internal organs of the body such as the heart and gut are integrated into a multimodal structure of interactions, based on predictive coding principles at several hierarchical levels. This complex structure of interactions is discussed in more detail in later sections. Allostatic load can be understood as a cost of sustaining allostasis [3.Quigley K.S. et al.Functions of interoception: from energy regulation to experience of the self.Trends Neurosci. 2021; 44: 29-38Abstract Full Text Full Text PDF PubMed Google Scholar]. The saturation of the allostatic load due to the cumulative burden of chronic stress and life events is referred to as allostatic overload. In this state, the organism is exposed to repeated environmental demands evoking chronic neural and neuroendocrine responses [7.Guidi J. et al.Allostatic load and its impact on health: a systematic review.Psychother. Psychosom. 2020; 90: 11-27Crossref PubMed Scopus (147) Google Scholar]. Behavioral examples of allostatic overload include over-reacting and under-reacting to environmental stressors. Allostatic overload can be assessed using various measures at different levels of description (Figure 2B). These include: (i) cerebral measurements using brain structure and connectivity metrics [4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar]; (ii) cardiocerebral estimations of the brain's responses to sensing the heart [20.Coll M.P. et al.Systematic review and meta-analysis of the relationship between the heartbeat-evoked potential and interoception.Neurosci. Biobehav. Rev. 2021; 122: 190-200Crossref PubMed Scopus (30) Google Scholar]; (iii) peripheral blood biomarkers [21.Shiels P.G. et al.Circulating markers of ageing and allostatic load: a slow train coming.Pract. Lab. Med. 2017; 7: 49-54Crossref PubMed Scopus (0) Google Scholar,22.Wright K.D. et al.Beyond allostatic load: focused biological measures of chronic stress in African American older adults.Res. Gerontol. Nurs. 2021; 14: 222-224Crossref PubMed Scopus (1) Google Scholar]; and (iv) psychological measures testing the relations between subjective and objective arousal [4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar] and clinical psychosocial assessments evaluating dysregulated responses to environmental demands [23.Piolanti A. et al.Use of the psychosocial index: a sensitive tool in research and practice.Psychother. Psychosom. 2016; 85: 337-345Crossref PubMed Scopus (34) Google Scholar,24.Fava G.A. et al.Current psychosomatic practice.Psychother. Psychosom. 2017; 86: 13-30Crossref PubMed Scopus (144) Google Scholar]. At the cerebral level (Figure 2B), different measures of anatomical/structural and functional connectivity can quantify the degree of interaction between the nodes that form the AIN. For instance, the integrity of the AIN and its main hubs can be measured using methods such as voxel-based morphometry, diffusion tensor imaging, and rsfMRI [4.Kleckner I.R. et al.Evidence for a large-scale brain system supporting allostasis and interoception in humans.Nat. Hum. Behav. 2017; 1: 0069Crossref PubMed Scopus (213) Google Scholar]. The cardiocerebral level (Figure 2B) could be partially indexed by the heart-evoked potential (HEP), a marker of interoceptive and brain–body regulation processes characteristic of brain responses activated by visceral signals and regulated by the ability to feel the body [20.Coll M.P. et al.Systematic review and meta-analysis of the relationship between the heartbeat-evoked potential and interoception.Neurosci. Biobehav. Rev. 2021; 122: 190-200Crossref PubMed Scopus (30) Google Scholar]. Neuroimaging and electroencephalography source localization studies [25.Pollatos O. et al.Brain structures involved in interoceptive awareness and cardioafferent signal processing: a dipole source localization study.Hum. Brain Mapp. 2005; 26: 54-64Crossref PubMed Scopus (170) Google Scholar,26.Al E. et al.Heart-brain interactions shape somatosensory perception and evoked potentials.Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 10575-10584Crossref PubMed Scopus (48) Google Scholar] associate the HEP with brain structures supporting allostatic and interoceptive processes. In addition to traditional active heartbeat detection tasks, where participants must press a key each time they feel a heartbeat [27.García-Cordero I. et al.Feeling, learning from and being aware of inner states: interoceptive dimensions in neurodegeneration and stroke.Philos. Trans. R. Soc. Lond. Ser. B Biol. 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